The biguanide antihyperglycemic agent metformin is concurrently marketed in the U.S. in the form of its hydrochloride salt (Glucophage.TM., Bristol-Myers Squibb Company).
Metformin hydrochloride is a cohesive white powder which is highly soluble in water (&gt;300 mg/ml at ambient temperature), has a hygroscopicity measured at 95% relative humidity /25.degree. C. of greater than 20% moisture uptake at 6 hours, and a high compaction susceptibility. Accordingly, handling of metformin hydrochloride in a pharmaceutical manufacturing facility could present problems especially in high humidity environments. Furthermore, formulation of the metformin hydrochloride in a controlled release system is exceedingly difficult due, at least in part, to its extremely high water solubility.
The currently marketed metformin hydrochloride salt has a pronounced saline, bitter taste. Accordingly, it is usually marketed as a coated tablet where the coating is designed to mask any unpleasant taste. However, where the metformin hydrochloride salt is in the form of scored-divisible tablets, it will not usually have a coating or outer layer to mask the unpleasant taste.
Taste is of primary concern where the metformin hydrochloride is to be formulated as a chewable tablet or liquid indicated for children or adults who are not able to swallow tablets.
In such cases, the unpleasant taste of the hydrochloride salt could lead to compliance problems.
The prior art is replete with references disclosing metformin salts of various organic or inorganic acids in a 1:1 molar ratio of metformin:acid. Thus, for example, U.S. Pat. No. 3,174,901 discloses phosphate, sulfate, hydrobromide, salicylate, maleate, benzoate, succinate, ethanesulfonate, fumarate and glycolate salts of metformin;
U.S. Pat. No. 4,835,184 discloses the p-chlorophenoxyacetic acid salt of metformin;
French Patent Nos. 2320735 and 2037002 disclose the pamoate salt of metformin;
French Patent No. 2264539 and Japanese Patent No. 66008075 disclose the orotate salt of metformin;
French Patent No. 2275199 discloses the (4-chlorophenoxy) isobutyrate salt of metformin;
U.S. Pat. No. 4,080,472 discloses the clofibrate salt of metformin;
U.S. Pat. No. 3,957,853 discloses the acetylsalicylate salt of metformin;
French Patent No. 2220256 discloses the theophyllin-7-acetate salt of metformin;
German Patent Nos. 2357864 and 1967138 disclose the nicotinic acid salt of metformin;
U.S. Pat. No. 3,903,141 discloses the adamantoate salt of metformin;
Japanese Patent No. 69008566 discloses the zinc-chlorophyllin salt of metformin;
Japanese Patent No. 64008237 discloses hydroxy acid salts of metformin, including salts of hydroxy aliphatic dicarboxylic acids such as mesotartaric acid, tartaric acid, mesoxalic acids, and oxidized maleates;
Japanese Patent No. 63014942 discloses the tannic acid salt of metformin;
Japanese Patent Nos. 87005905 and 61022071 disclose the 3-methyl-pyrazole-5-carboxylic acid (or other 5-members hetercycle carboxylic acid) salt of metformin;
Romanian Patent No. 82052 discloses sulfamido aryloxyalkyl carboxylic acid salts of metformin;
Soviet Union Patent No. 992512 discloses the trimethoxy benzoic acid salt of metformin;
U.S. Pat. No. 4,028,402 discloses the dichloroacetic acid salt of metformin.
U.S. Pat. No. 5,631,224 to Efendic et al issued May 20, 1997, discloses a combination of metformin with GLP-1(7-36) amide, or GLP-1(7-37) or a fragment thereof which retains GLP-1(7-37) activity.